Chronic rejection is the most common cause of allograft loss after the first year of transplantation. The characteristic lesion of chronic rejection is transplant vascular sclerosis (TVS) that is characterized by expansion of the intimal layer of muscular arteries (fibrointimal hyperplasia). TVS occurs in cardiac, renal, pancreatic and more rarely hepatic allografts. Fibrointimal hyperplasia also occurs in blood vessels exposed to a variety of insults such as direct trauma, hemodynamic stress, and atherosclerosis. Based on these observations, we postulate the fibrointimal hyperplasia represents remodeling of the blood vessel wall in response to any type of vascular injury, immunologic or non-immunologic. In the present study we propose to focus on the role of the complement system and/or anti-graft antibodies in the production of graft vascular injury. Specifically, we propose to explore the following hypothesis/aims: 1) The initial damage to the allograft's muscular arteries is due to ischemia and reperfusion, and that damage is mediated in large part by activation of the complement system. We postulate that complement activation during reperfusion is due to the loss of complement regulatory proteins from ischemic cells. These proteins normally inhibit complement activation and prevent complement mediated cell damage. In addition, we postulate the complement-mediated vascular damage can lead to fibrointimal hyperplasia in allograft vessels. 2) We postulate that complement activation generates C5a that can interact directly with vascular smooth muscle cells (VSMC) causing cell migration into the intima, cell proliferation, and production of growth factors. This postulate is based on recent observations from our laboratory showing that VSMC have receptors for C5a. 3) Anti-graft antibodies, by activating the complement system in graft vessels, cause vascular injury and lead to TVS. We propose to study two types of antibodies: Anti-MHC, and anti-head shock protein 60 (HSP60) antibodies. Our interest on the latter is based on the observation that anti-HSP60 antibodies appear to participate in the pathogenesis of atherosclerosis, a lesion with many of the characteristics of TVS. Furthermore conditions associated with transplantation can cause up-regulation of HSP60 and high anti-HSP60 antibodies titers. The present proposal addresses new hypotheses and will explore mechanisms by which complement and antibodies may lead to TVS. These humoral effector systems interact with macrophages (Dr Wewers), lymphocytes (Dr Orosz) and VSMC (Dr Strauch). Thus, these studies are best understood in the context of the other pathogenic factors that we propose to investigate in this program project.